The long-term objectives of this program are to identify the immunogenetic mechanisms, possible etiologic agent(s) and the natural history of the interplay of autoimmunity and the islets of Langerhans, as it relates to the pathogenesis of insulin dependent diabetes (IDDM). This information may be useful in developing immunologic and genetic predictors of individuals with high risk for the eventual development of IDDM, and may allow for the identification of potential environmental factors that might precipitate an ongoing defect in autoimmunity in such individuals. Such cause and effect identifications might then permit for appropriate support of beta cell function on one hand and the targeting of specific preventive immunotherapies on the other. The basic approach to understanding this problem has been longitudinal studies in sets of monozygotic twins discordant for IDDM. An important part of the program since its inception in 1964 has been the preservation of biologic materials (frozen serum samples) from each and every encounter. A second factor has been the performance of in-depth perturbation of the function of the endocrine pancreas serially two to three times a year. Methods have been developed and refined allowing the detailed quantification of the early phase insulin release (to multiple secretagogues) and it has been discovered that a slow progressive loss of beta cell function occurs several years prior to the development of overt clinical IDDM. Several qualitative and quantitative markers for autoimmunity and beta cell destruction have been developed and validated. This proposal envisions the continuation into the 23rd and subsequent years of the prospective monozygotic twin-IDDM pathogenesis study. In addition to the periodic evaluation of the currently enrolled discordant and concordant twins, recruitment and study of new twin pairs will be intensified. Focus will be directed towards the characterization of the pathogenetic events and processes surrounding the initiation of abnormal islet cell autoimmunity (e.g., conversion from autoantibody-negativity to positivity) and beta cell dysfunction in the currently discordant twins. Studies to further define genetic/immunogenetic mechanisms and to develop novel predictive serologic and cellular immunoassays will be continued. Finally, this model investigative system of monozygotic twins will be extended to other groups (e.g., non-diabetic first degree relatives) also at higher risk for the development of IDDM.